The primary goal of this application is to understand how the RNA editing enzymes called Adenosine Deaminases that act on RNA (ADARs) function in the nervous system. Caenorhabditis elegans will be used for these studies, and strains lacking all ADARs have been isolated and found to exhibit behavioral defects. To correlate expression of ADARs in particular neurons with particular behaviors, ADARs will be expressed in specific neurons of mutant strains, and phenotypic rescue monitored. Other studies will focus on determining the relevant edited RNAs. Microarray analyses and inosine-specific cleavage strategies are proposed. These methods will identify inosines in coding as well as non-coding regions of mRNAs, but the latter will be the focus of further study. Experiments to determine how mRNAs with inosines in non-coding sequences are metabolized in vivo, and how this metabolism changes in the absence of RNA editing will be performed. Recent experiments indicate ADARs intersect with RNA interference pathways, and possible mechanisms for this will be tested. Understanding the molecular determinants of behavior is one of the last frontiers of molecular biology. This application offers the potential for new discoveries in behavior, gene silencing and the general roles of dsRNA in cells.